Classifications

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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
  • A61B10/02—Instruments for taking cell samples or for biopsy
  • A61B10/04—Endoscopic instruments
• • A—HUMAN NECESSITIES
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  • A61B1/00002—Operational features of endoscopes
  • A61B1/00011—Operational features of endoscopes characterised by signal transmission
  • A61B1/00016—Operational features of endoscopes characterised by signal transmission using wireless means
• • A—HUMAN NECESSITIES
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  • A61B1/00147—Holding or positioning arrangements
  • A61B1/00156—Holding or positioning arrangements using self propulsion
• • A—HUMAN NECESSITIES
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  • A61B10/0045—Devices for taking samples of body liquids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
  • A61B10/02—Instruments for taking cell samples or for biopsy
• • A—HUMAN NECESSITIES
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  • A61B5/15—Devices for taking samples of blood
  • A61B5/157—Devices characterised by integrated means for measuring characteristics of blood
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
• • G—PHYSICS
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  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
  • G01N33/54366—Apparatus specially adapted for solid-phase testing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
  • A61B2017/00017—Electrical control of surgical instruments
  • A61B2017/00022—Sensing or detecting at the treatment site
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
  • A61B17/00234—Surgical instruments, devices or methods, e.g. tourniquets for minimally invasive surgery
  • A61B2017/00345—Micromachines, nanomachines, microsystems
• • A—HUMAN NECESSITIES
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  • A61B34/30—Surgical robots
  • A61B2034/301—Surgical robots for introducing or steering flexible instruments inserted into the body, e.g. catheters or endoscopes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
  • A61B34/30—Surgical robots
  • A61B2034/303—Surgical robots specifically adapted for manipulations within body lumens, e.g. within lumen of gut, spine, or blood vessels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M25/00—Catheters; Hollow probes
  • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
  • A61M25/09—Guide wires
  • A61M2025/09175—Guide wires having specific characteristics at the distal tip
  • A61M2025/09183—Guide wires having specific characteristics at the distal tip having tools at the distal tip
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B21—MECHANICAL METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL; PUNCHING METAL
  • B21F—WORKING OR PROCESSING OF METAL WIRE
  • B21F3/00—Coiling wire into particular forms
  • B21F3/02—Coiling wire into particular forms helically
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B21—MECHANICAL METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL; PUNCHING METAL
  • B21F—WORKING OR PROCESSING OF METAL WIRE
  • B21F45/00—Wire-working in the manufacture of other particular articles
  • B21F45/008—Wire-working in the manufacture of other particular articles of medical instruments, e.g. stents, corneal rings
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B21—MECHANICAL METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL; PUNCHING METAL
  • B21F—WORKING OR PROCESSING OF METAL WIRE
  • B21F7/00—Twisting wire; Twisting wire together
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
  • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases

Definitions

• the invention relates in some aspects to a collector for biological material including markers.
• PCT Pub. No. WO2013/176730 to Life Technologies incorporated by reference in its entirety, teaches a method in which antibodies have been engineered to include a specific protease cleavage site in the hinge region which allows cell release with a specific protease which does not affect the cells significantly.
• Alternative binding molecules such as scaffold molecules have also been described which overcome some of the limitations of antibodies. These are proteins of small size, single-chain structure, and few posttranslational modifications.
• vascular catheters used for medical interventions usually have a cylindrical shape.
• the advantage of this form is the relatively low frictional resistance.
• this form narrows the flow of blood in small vessels and may increase the risk of thrombosis.
• U.S. Pat. Pub. No. 2012/0237944 Al to Luecke et al. incorporated by reference in its entirety, discloses a detection device for the in vivo and/or in vitro enrichment of sample material, in which a functional surface covered with detection receptors has a three- dimensional structure with opposing functional sections forming liquid covered gaps.
• the individual sections of the functional surface can be equipped with chemically identical or different detection receptors, and the opposing functional sections form liquid covered gaps.
• a biomaterial collection device can include, for example, a wire that includes a functional member that can include a proximal end, a distal end, a first flat surface and a second flat surface opposing the first surface.
• the functional member can be configured to fit within a body lumen.
• the functional member can include binding elements configured to bind circulating biomaterials of interest.
• the functional member can also include curved portions/windings that form revolutions around the longitudinal axis of the device.
• the wire can include from about 3 revolutions to about 5 revolutions per 1 cm of length of the wire, or about 4 revolutions per 1 cm of length of the wire.
• the wire can be a metal, such as stainless steel or Nitinol in some cases.
• the probe can also include a proximal handle that does not include binding elements, and an atraumatic distal end.
• the functional member can also include a third surface and a fourth surface, the third surface and the fourth surface each adjacent the first surface and the second surface.
• the third surface and the fourth surfaces can be flat surfaces, or not flat (e.g., rounded surfaces), and not contain binding elements in some cases.
• an in vivo biomaterial collection device that can include a proximal end, a distal end, a first surface and a second surface opposing the first surface.
• the functional member can be configured to fit within a body lumen.
• the functional member can include binding elements configured to bind circulating biomolecules and cells.
• the functional member can include curved portions that form revolutions around the longitudinal axis of the device; and a collar operably connected to the proximal end of the helical functional member.
• the collar can be configured to stably position the device within a body lumen.
• the functional member can have a circular cross- section, or a non-circular, e.g., square or rectangular cross section in some embodiments.
• the device can also include a filter operably connected to the collar to isolate cells according to their size, such that it can also can change the blood flow.
• the binding elements can include fusion proteins, nucleic acids, biological probes, or synthetic material probes.
• the helical functional member can be coupled to, or be part of a guidewire.
• the guidewire can include a metallic and/or polymeric material.
• an in vivo biomaterial collection device can include a functional member that includes a proximal end, a distal end, a first surface and a second surface opposing the first surface.
• the functional member can be configured to fit within a body lumen.
• the functional member can include binding elements configured to bind circulating biomolecules and cells.
• the functional member can also include curved portions that form revolutions around the longitudinal axis of the device.
• the functional member can be transformable from a first curved configuration to a second configuration more linear than the first configuration. In some embodiments, the second configuration has a greater axial length than the first configuration.
• the functional member can include a shape memory material.
• the device is transformable from the second configuration to the first configuration via exposure to body temperature.
• the device can also include a plurality of flaps operably connected to the distal end of the functional member.
• the flaps can include apertures configured to filter blood.
• the device can also include a control line operably connected to the flaps.
• the flaps can be movable between a first radially compressed configuration to a second radially expanded configuration.
• the functional member can include a bifunctionally charged carrier.
• the control line can run at least partially through one or more eyelets on the functional member, or at least partially through one or more apertures on the functional member.
• a method for collecting markers associated with disease can include, for example, providing a probe comprising a wire comprising a functional member comprising a proximal end, a distal end, a first flat surface and a second flat surface opposing the first surface, wherein the functional member comprises binding elements configured to bind circulating biomaterials of interest, wherein the functional member comprises curved portions that form revolutions around the longitudinal axis of the device, wherein the binding elements have affixed thereto at least one binding partner for binding a marker, and wherein the binding surface is configured to immobilize a marker to the binding surface upon binding of the marker to the binding partner; positioning at least a portion of the probe in an anatomical structure of a living organism; maintaining the probe in a generally fixed position; and removing the probe from the living organism.
• FIG. 1 illustrates a lateral view of one embodiment of an in vivo collector that has a functional surface with a spiral or helical shape and an umbrella-like sieve and collar.
• Fig. 2 illustrates a lateral view of one embodiment of the functional surface of an in vivo collector, which has a helical or conical shape.
• FIG. 3 illustrates various views of an embodiment of an in vivo collector having a flattened, e.g., flat wire.
• FIGs. 3A-3C illustrate various views of an embodiment of a collector having a flat wire configuration.
• FIGs. 3D-3H illustrate experimental data and a testing system relating to an embodiment of a collection probe.
• FIG. 4 illustrates another schematic embodiment of a detection device that can include an elongate functional member which can have generally opposing functional surfaces as shown.
• FIG. 5 illustrates an embodiment of a detection device similar to that of
• FIG. 6 schematically illustrates a detection device with blood flowing inside a lumen of, as well as outside of a functional member having a generally cylindrical cross-section.
• FIG. 7 schematically illustrates a coiled functional member as part of a detection device with slots or other spaces in between revolutions of the coils, attached proximally to a tether line.
• Fig. 8 illustrates schematically the embodiment of Fig. 7, wherein blood can flow inside the lumen of, outside of, and through the slots and spaces in between revolutions of the coils.
• Figs. 9A-9R illustrate various components of a flow system that can include one or more probes therethrough for in vitro collection of a patient specimen.
• Some embodiments of the present invention generally provides improved devices and methods for detecting and/or reversibly capturing rare cells, molecules, tumor markers, and other biomaterials from body fluids in vitro, ex vivo, or in vivo over time.
• Embodiments of the invention include a collector device configured for placement within a living organism (or in vitro using a sample from a living organism) for a period of time to provide sufficient yield of biological markers from any body fluid for analysis.
• the functional surface has a first, substantially linear configuration for insertion into a body lumen, such as an artery or vein for example.
• a body lumen such as an artery or vein for example.
• the functional surface which can include a shape memory material can transform to a second, substantially nonlinear configuration, such as a coiled configuration, which can advantageously have an increased surface area for retaining cells or other markers of interest.
• the coiled configuration can have an axial length that it shorter than that of the substantially linear configuration in some embodiments, similar to that of a compressed and extended spring.
• the wire can be rotated back or thru a temperature change to its original form, such as a rectangular wire form.
• the rare cells on the wire can be immunostained fluorescently labeled and the target cell can be identified, quantified and enumerated under a fluorescence microscope or related type reader on or off the wire. Subsequent statistical analysis enables reviewers to obtain potential diagnostic information.
• an in vivo biomaterial collection device can include, for example, a functional member comprising a proximal end, a distal end, a first surface and a second surface opposing the first surface.
• the functional member can be configured to fit within a body lumen.
• the functional member can include binding elements configured to bind circulating biomolecules and cells.
• the functional member can also include curved portions that form revolutions around the longitudinal axis of the device.
• the device can also include a collar operably connected to the proximal end of the helical functional member, the collar configured to stably position the device within a body lumen.
• the functional member can have a variety of cross-sections, including a circular, non-circular, square, or rectangular cross-section, for example.
• the device can also include a filter operably connected to the collar to isolate cells according to their size it also can change the blood flow.
• the binding elements can include fusion proteins, biological probes, and/or synthetic material probes.
• the helical functional member can be coupled to a guidewire, which can include a metallic and/or polymeric material, for example.
• the device can include a functional member that includes a proximal end, a distal end, a first surface and a second surface opposing the first surface.
• the functional member can be configured to fit within a body lumen.
• the functional member can include binding elements configured to bind circulating biomolecules and cells.
• the functional member can also include curved portions that form revolutions around the longitudinal axis of the device.
• the functional member can be transformable from a first curved configuration to a second configuration more linear than the first configuration. In some embodiments, the second configuration has a greater axial length than the first configuration.
• the functional member can include a shape memory material. The device can be transformable from the second configuration to the first configuration via exposure to body temperature.
• the device can also include a plurality of flaps operably connected to the distal end of the functional member.
• the flaps can include apertures configured to filter blood.
• the device can also include a control line operably connected to the flaps.
• the flaps can be movable between a first radially compressed configuration to a second radially expanded configuration.
• the functional member can include a bifunctionally charged carrier.
• the control line can run at least partially through one or more eyelets, or apertures, on the functional member.
• the devices, systems and methods described within this disclosure are, in some embodiments, generally for detecting and/or reversibly capturing cells, nucleic acids, biomolecules, and other biomaterials from body fluids(blood, csf, bone marrow, peritoneal/pleural cavity, bladder) in vivo over time.
• the captured material can then be analyzed for scientific or diagnostic purposes.
• the devices and methods described herein may be used for the early detection of occult cancer cells, infections, or other disease markers. However, they may also be used to detect, capture, or monitor any cell type or biomarker in any body fluid.
• the in vivo collecting device includes a spiral, helical, or conical shaped functional surface, which may enhance cell or biomarker binding from the blood while decreasing the risk of thrombosis.
• a spiral or helical flow of blood may decrease the concentration of platelets near the vessel wall, thereby reducing the risk of intravascular thrombosis. This effect could be synergistically improved by utilization of a flat wire or other surface, as disclosed elsewhere herein.
• the in vivo collecting device includes binding proteins on the functional surface that allow gentle cell release combined with specific binding and simple engineering.
• Fig. 1 illustrates one embodiment of an in vivo collecting device shown as it would sit inside a vein, artery, or another body lumen.
• the device may have one, two, or more functional surfaces with a spiral or helical shape 100.
• a spiral or helical shape is defined by a curve that is the locus of a point that rotates about a fixed point while continuously increasing its distance from that point.
• the functional surface may have a coiled shape.
• the number of coils may be varied.
• the coil structure may be formed linear or conical.
• the number of helices and the pitch may be variable.
• the diameter of the functional surface may be variable between about 0.3mm and about 5mm.
• the number of windings may vary with the length and pitch of the coil.
• the diameter (or height or width) of the wire material may be, in some embodiments, variable between about 0.1mm and 1.0 mm.
• the thickness of the wire may also change within the structure in order to vary the fluid dynamics within the range of the whole structure. If the shape of the functional surface is conical, the structure may vary in length between, for example, 1cm and 5cm.
• the coil pitch may be adjusted to gain a variable diameter between the windings.
• the functional surface may have a shape other than spiral, helical, or conical.
• the detection area is coated with a biocompatible coating with protein repellent properties.
• the coating may include, for example, synthetic (e.g. Polycarboxylate brush structures) or natural (e.g. alginate) polymers that form a hydrogel or brush like structures.
• Fig. 2 illustrates one embodiment of the functional surface of the collection device that may include a coil 210 that is formed into a conical shape. Detection molecules that bind rare cells or other biomarkers 205 may be operably connected to the coil.
• the narrow end of the spiral 200 is oriented in the direction of the blood stream, which results in the bloodstream and its circulating cells (CTC, circulating endothelial cells(CEC), stem cells, specific normal cells from organs), which can be rare, being slowed down.
• CTC circulating endothelial cells
• stem cells specific normal cells from organs
• the functional surface of the device may feature detection biomolecules that are operably connected to its surface 105 and 110.
• the detection molecules may be designed to bind rare cells, nucleic acids, exosomes, and/or other biomarkers.
• the detection molecules may be of one, two, or more types.
• the detection molecules may be antibodies or other proteins or nucleic acid or synthetic/natural mimics of all.
• the detection device may have an umbrella-like collar 115, such as proximal or distal to the functional surface of the device.
• the collar 115 can be radially expandable, and may permit adjustment of the device to the diameter of a blood vessel or other body lumen to prevent migration of the detection device.
• the detection device may have an umbrella-like sieve 120 positioned, for example, proximal or distal to the collar.
• the collar 115 has a funnel shape as shown, with a decreasing diameter from a proximal to a distal end to direct flow into the sieve 120.
• the collar 115 can have a central lumen to allow fluid flow therethrough.
• the functional surface 100 which can be a wire in some embodiments, can be operably attached to the collar 115 at its proximal end, and fluid can flow in one or more openings around the attachment to the collar 115.
• the sieve 120 can be operably attached at its proximal end to the distal end of the collar 115.
• the sieve 120 can also serve as a functional surface to bind materials of interest.
• the sieve 120 has apertures to allow for flow through the sieve 120 while being able to trap some materials of interest within the sieve 120.
• Figure 3 illustrates another schematic embodiment of a detection device 300 having a rectangular or square cross-section partially or completely along the axial length of the elongate functional surface.
• the device 300 can also include one, two, or more lumens, such as central lumen 306 to allow blood to flow therethrough, the sidewall of the lumen 306 surrounded by functional surfaces 302.
• blood can also flow radially outwardly of the outer wall of the functional surfaces 302, and capture of markers, cells, or other materials can occur along the outer wall as well as inside the central lumen.
• a tether line 305 with one, two, three, or more distal forked extensions 304 operably connected to the proximal end of the functional surface 302 as illustrated.
• the functional element 302 can have a cross-sectional width of about 4mm, such as between about 1mm and about 10mm, between about 2mm and about 6mm, or between about 3mm and about 5mm, with functional area walls having cross- sectional widths of about 1mm each, such as between about 0.1mm and about 5mm each, or between about 0.5mm and about 2mm each.
• Some embodiments are directed to enhancements to existing in vivo devices.
• many existing devices are shaped in a round form (circular cross-section) like a biopsy needle. With these devices it can be potentially very difficult to do direct immuno staining or visualization for characterization of specific captured cells afterwards.
• Disclosed herein, in some aspects, are imaging target components on an in- vivo detector.
• a device includes a "flat" medical wire, configured after the functionalization of the flat wire it can rotate 360 degrees about the central axis of the wire and the length of the wire, as illustrated for example in Figure 3.
• the wire does not have a circular cross-section, but rather can be oval or ellipsoid in some embodiments.
• a "flat" wire can include a substantially square or rectangular cross-section partially or entirely along the length of the functional surface.
• the wire can have a length, a width, and a thickness, wherein the width is about or at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 6x, 7x, 8x, 9x,10x, or more (or ranges incorporating any two of the aforementioned values) relative to the thickness of the wire at a selected cross-section transverse to the longitudinal axis of the wire.
• the wire is solid/has a solid core, that is, it does not include an aperture or central lumen.
• the number of rotations (which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) can vary depending on the desired clinical result and per a given length (such as windings per cm, for example); this can allow to adapt to different vein blood flow rates, more rotation can mean a reduced flow rate along the medical wire.
• the wire can have a first dimension, such as a width, of between about 0.1mm and about 5mm, between about 0.25mm and about 3mm, between about 0.50mm and about 3cmm, between about 0.50mm and about 2mm, between about 0.50mm and about 1.5mm, between about 1mm and about 2mm, between about 0.60mm and about 1.50mm, about 0.60mm, 0.70mm, 0.80mm, 0.90mm, 1.00mm, 1.10mm, 1.20mm, 1.30mm, 1.40mm, 1.50mm, or other ranges incorporating any two of the aforementioned values depending on the desired clinical result.
• a first dimension such as a width, of between about 0.1mm and about 5mm, between about 0.25mm and about 3mm, between about 0.50mm and about 3cmm, between about 0.50mm and about 2mm, between about 0.50mm and about 1.5mm, between about 1mm and about 2mm, between about 0.60mm and about 1.50mm, about 0.60mm, 0.70mm, 0.80mm, 0.90mm, 1.00mm,
• the wire can have a second dimension, such as a thickness or height, of between about 0.05mm and about 1mm, between about 0.05mm and about 0.5mm, between about 0.05mm and about 0.3mm, between about 0.10mm and about 0.30mm, or about 0.10mm, 0.12mm, 0.14mm, 0.16mm, 0.18mm, 0.20mm, 0.22mm, 0.24mm, 0.26mm, 0.28mm, 0.30mm, or ranges incorporating any two of the aforementioned values depending on the desired clinical result.
• a second dimension such as a thickness or height
• Sample non-limiting width and thickness dimensions for a wire can be, in some embodiments, about 0.80mm x 0.15mm for an in vivo application, or 1.32mm x 0.18mm for an in vitro flow system application, although other dimensions are also possible as noted above.
• the functional member can include a shape memory material, such as Nitinol or a shape memory polymer, for example.
• Shape memory materials are smart materials that have the ability to return from a deformed state (temporary shape) to their original (permanent) shape induced by an external stimulus (trigger), such as temperature change.
• a NiTi shape memory metal alloy can exist in two different temperature-dependent crystal structures (phases) called martensite (lower temperature) and austenite (higher temperature or parent phase).
• martensite lower temperature
• austenite higher temperature or parent phase.
• austenite finish temperature Af
• austenite NiTi When austenite NiTi is cooled, it begins to change into martensite.
• martensite start temperature Ms
• martensite finish temperature Mf
• the functional surface is coated by one, two, or more polymers, of which one, two, or more binding agents can be attached thereto.
• a probe 330 can include a wire that can be a flat wire in some cases.
• the probe 330 can include a plurality of flat segments 380 interspersed by winding sections 381 as the wire is twisted around itself as shown.
• the flat segments 380 can be generally parallel to the longitudinal axis 383 of the wire in some embodiments.
• the probe can have between about 1 and about 10 windings, between about 1 and about 8 windings, between about 1 and about 6 windings, between about 2 and about 6 windings, between about 3 and about 5 windings, about 4 windings, or about 2, 3, 4, 5, 6, 7, 8, 9, or 10 windings (all of the foregoing with respect to a particular length of the wire, such as per about 1cm of length of the wire in some embodiments).
• the entire probe, the entire functional area of the probe, or a portion of the functional area of the probe can be made of a flat wire that includes a number of windings as disclosed herein. The windings can be regularly and/or irregularly spaced apart in some embodiments.
• Figure 3A schematically illustrates a probe 330 within a blood vessel 340 and configured to collect materials of interest, such as circulating tumor cells for example.
• Figure 3B schematically illustrates a probe 330 within a urine specimen for collection of, for example, fDNA. The collection can occur, for example in a probe within the bladder such as an indwelling Foley catheter, or completely external to the bladder, such as in a urine specimen container.
• the wire includes between about 12 windings and about 20 windings per 4 cm of length of the wire, such as between about 13 windings and about 19 windings per 4 cm of length of the wire, between about 14 windings and about 18 windings per 4 cm of length of the wire, between about 15 windings and about 17 windings per 4 cm of length of the wire, or about 12, 13, 14, 15, 16, 17, 18, 19, or 20 windings per 4 cm of length of the wire, or ranges incorporating any two of the aforementioned values.
• Figure 3C illustrates a cross-section through a flat segment of the wire 330 of the probe of Figures 3 A and 3B, according to some embodiments of the invention, with first 351 and second 352 opposing functional surfaces that can be flat or substantially flat as previously described, and parallel or substantially parallel to each other as illustrated.
• the lateral third 353 and fourth surfaces 354 of the wire can be straight, or rounded as illustrated in some embodiments as shown to be less traumatic to the body lumen of interest.
• the lateral third 353 and fourth 354 surfaces can be functional surfaces or nonfunctional (e.g., do not serve as binding surfaces for material detection or collection). In other words, in some embodiments, less than the entire perimeter of the functional surface of the binding surface serves as a binding surface for materials of interest.
• the binding surface may be configured with an increased surface area to provide an increased number of binding sites on the probe, such as described, for example in U.S. Pat. No. 8,084,246 to Hoon et al., which is hereby incorporated by reference in its entirety.
• the surface area may be increased by providing an increased longitudinal length, increased diameter or cross-section through at least a portion of the distal zone.
• at least a portion of the distal zone may comprise a porous material and/or micro structure to increase the surface area.
• the binding surface does not include an increased surface area (e.g., lacks pores and/or a microstructure) and can have, for example, a smooth, uninterrupted, and/or continuous surface.
• the device includes, or does not include any of the following structures: a spiral, screw-shaped, worm-shaped, undulated, helical, filamentous, brush-like, comb-like, net-like, porous, spongy or similar structures.
• experiments were performed to determine the influence of different number of windings on in vitro cell binding.
• Human umbilical cord endothelial cells (HUVEC) were bound to anti-CD 146 coated probes (BM Probe02) in flow system with cell culture medium. The influence of the number of windings on a 4 cm length of a 1 mm flat steel wire was tested.
• the flow system was set up, including a cell suspension, holder for 6 probes, and a peristaltic pump along a flow system loop, as shown schematically in Figure 3D.
• the flow velocity was 1 cm/s in the experiments.
• the tubing diameter was 2 mm.
• the tubing diameter was 3 mm.
• the cells were suspended in cell culture medium with FBS and additives.
• 4 wires were introduced in the flow system at the same time.
• the wires were tested in a randomized approach, e.g., wires with different windings were mixed in each run.
• HUVEC were cultivated to a confluence of 90 - 100%.
• Figure 3E is a graphical analysis of results of experiment 2 showing rank distribution, while Figure 3F is a boxplot of the data.
• Figure 3G is a graphical analysis of results of experiment 3 showing rank distribution, while Figure 3H is a boxplot of the data.
• FIG. 4 illustrates another schematic embodiment of a detection device 400 that can include an elongate functional member 402 which can have generally opposing functional surfaces as shown.
• the functional member 402 can have a square, rectangular, or other cross-section as previously described.
• the distal end of the functional surface can support a sieve 404 with apertures to allow fluid flow therethrough, as well as to bind materials of interest.
• the sieve 404 can include a plurality of flaps/extensions 406 having apertures therethrough, such as 2, 3, or 4 extensions, and having longitudinal axes that are substantially orthogonal or at other angles to the functional member 402.
• the surfaces of the sieve 404 can also serve as functional surfaces.
• the flaps 406 can be regularly or irregularly spaced apart, such as spaced apart by 60, 90, 120, or 180 degrees in some cases.
• the distal ends of the flaps 406 can be operably connected to one or more tension members 408, which can allow the flaps 406 to radially open, or fold back/close such as proximally back toward the functional member 402 and close to allow for a decreased crossing profile advantageous for removal of the device 400.
• the tension members 408 can run through apertures 410 (as shown in the upper figure), eyelets 412 (as shown in the lower figure), channels, or other elements axially along the functional surface, through the functional member, or otherwise for enhanced control in some cases.
• the functional member can include one, two, or more binding members, such as a bifunctionally charged functional member as illustrated schematically 414.
• Figure 5 illustrates an embodiment of a detection device 500 similar to that of Figure 4, with an elongate functional member 502 having a width that can be at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, or more with respect to the thickness of the elongate functional member.
• the distal end of the elongate functional member can be operably attached to a plurality of flaps as previously described, which can move radially outwardly or inwardly via tension members operably connected proximally to a control actuated by an operator.
• the flaps 504 can form various shapes depending on the desired clinical result, such as a cross as shown.
• Figure 6 schematically illustrates a detection device 600 with blood flowing inside a lumen of, as well as outside of a functional member having a generally cylindrical cross-section.
• the sidewall of the lumen can be frustoconical or another geometry, having a first wider diameter proximally gradually or stepwise narrowing to a second narrower diameter distally as illustrated in the lower figure.
• FIG. 7 schematically illustrates a coiled functional member 702 as part of a detection device 700 with slots 704 or other spaces in between revolutions 706 of the coils, attached proximally to a tether line 708.
• the coiled functional member 702 can include a shape memory material allowing it to curl/twist/roll within the body lumen (e.g., via exposure to body temperature, induction, or other forms of heating) and uncurl/untwist/roll when removed from the body.
• removal of the detection device can involve cooling the functional member to allow for the transformation to a relatively straightened configuration (e.g., via injection of media such as cold saline into the target blood vessel, conduction cooling, etc.).
• Figure 8 illustrates schematically the embodiment of Figure 7, wherein blood can flow inside the lumen of, outside of, and through the slots and spaces in between revolutions of the coils.
• the functional surface can include a bifunctionally charged carrier in some cases as previously described herein.
• the detection or collection device can include an atraumatic distal tip, in order to avoid cutting or puncturing the body lumen, such as a blood vessel including an artery or vein for example.
• the atraumatic tip can be a rounded and/or blunt tip.
• the etching step can be performed manually or automated as well.
• the tip (for example, about or up to about 3 to about 4mm in some cases) of each wire can be placed for a desired period of time, such as a few seconds in concentrated acid (e.g., sulfuric or nitric acid). After etching the tips of the wires, the wires can then be washed in a solution such as ultra clean water in order to stop the process and remove acid residues from the surface.
• a guide element or wire that includes a functional surface can be used to insert the structure into an anatomical structure such as human body lumen or solid tissue, such as, for example, an artery, vein, lymphatic, or other body lumen via, for example, a percutaneous route or a cut-down procedure, or within the lumen of an input port such as an intravenous catheter placed prior to or concurrent with the probe.
• the probe can be fully inserted into the desired body lumen, or partially inserted with the functional surface fully within the target region of interest of the body in some cases, while a proximal non-functional region of the probe may remain outside of the body.
• the wire can include in some embodiments a proximal handle or hub that can remain outside of the body while the probe is inserted into the body lumen for a desired period of time, such as about, at least about, or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, 360, or more minutes.
• the probe can be maintained in a fixed position for the desired period of time, or moved in some embodiments.
• the probe can then be removed from the body lumen in some embodiments.
• the probe is detached from a proximal handle and partially or fully maintained within the body lumen for a period of time, and then retrieved with a separate retrieval tool later.
• an 18 gauge is inserted into the basilica vein, cephalic vein, or medial cubital vein, all located in the antecubital fossa in the arm.
• the stylet is removed from the peripheral venous IV and discarded.
• a cap of the probe is removed and a connector of the probe is screwed or otherwise removably attached to the IV.
• the probe is carefully inserted into the vein through the IV until a second mark location/location is reached. In this position, the functional area of the probe will be in the vein.
• the probe can be removed after, for example, 30 - 60 minutes through the IV, after that IV can be removed.
• the probe can then be processed and sent for analysis.
• the probe can be described in some cases in terms of an insert to be temporarily placed down an existing access port or sheath into the cardiovascular system, for retrieving a marker from blood, broader applicability is also possible in some embodiments.
• Existing access ports or sheaths include but are not limited to Hickman catheters, Portacath catheters, peripherally inserted central catheter (PICC) lines, femoral, jugular, or subclavian central venous lines, radial arterial catheters and peripheral venous lines.
• PICC peripherally inserted central catheter
• femoral femoral
• jugular jugular
• subclavian central venous lines femoral, jugular, or subclavian central venous lines
• radial arterial catheters and peripheral venous lines radial arterial catheters and peripheral venous lines.
• additional procedures such as transseptal puncture and transjugular intrahepatic puncture, may be used to access other body sites such as the arterial
• the probe may be adapted for direct access to a target site, without the use of a distinct tubular access catheter, in general, whether used with an access sheath or as a stand alone device, the dimensions of the probe can be optimized by persons of skill in the art in view of the present disclosure to suit any of a wide variety of target sites.
• a probe can be used to obtain samples from large and small arteries and veins throughout the cardiovascular system, as well as other lumens, potential spaces, hollow organs and surgically created pathways.
• Marker (tumor and/or non- tumor) collection may be accomplished in blood vessels, body lumens or cavities, such as the lymphatic system, esophagus, trachea, urethra, ureters, fallopian tubes, intestines, colon, biliary ducts, spinal canal and any other locations accessible by a flexible or rigid probe which may contain a specific binding partner of diagnostic value.
• the probe may also be adapted in some cases for direct advance through solid tissue, such as soft tissue or through bone, for site specific monitoring of a binding partner or binding partners of interest.
• the guide element may include, or be coated by a layer of one, two, or more of a metal, polymer, glass or a combination of materials.
• the metal could be, for example, Nitinol, Elgiloy, stainless steel, platinum, platinum/iridum, tungsten, gold, silver, or another material.
• the diameter of the guide element or wire is in the range of 0.1mm to 1mm and the overall length of the guide wire is 100mm to 200mm.
• the wire can have sufficient column strength to be advanced to a desired target site without undesirable bending or kinking.
• the conical and/or linear functional surface may be soldered (if it is composed of metal) or molded (if it is composed of polymer) to the guide element or wire.
• the conical structure is directly formed from the guide element or wire.
• binding partner refers to molecules that specifically bind other molecules (e.g., a marker of interest) to form a binding complex such as antibody-antigen, lectin-carbohydrate, nucleic acid-nucleic acid, biotin-avidin, etc. In certain embodiments, the binding is predominantly mediated by covalent or noncovalent (e.g. ionic, hydrophobic, etc.) interactions.
• binding partner(s) can be affixed in the binding zone on the probe of the invention. The binding partner(s) can be selected based upon the target marker(s) that are to be identified/quantified.
• the binding partner is preferably a nucleic acid or a nucleic acid binding protein.
• the binding partner is preferably a receptor, a ligand, or an antibody that specifically binds that protein.
• the binding partner is preferably a lectin, and so forth.
• a device of the invention can include several different types of binding partners, for example, multiple nucleic acids of different sequence and/or nucleic acids combined with proteins in the same device. The latter would facilitate, e.g., simultaneous monitoring of gene expression at the mRNA and protein levels. Other combinations of different types of binding partners can be envisioned by those of skill in the art and are within the scope of the invention.
• the binding partner may be combined with an optically sensitive dye to facilitate assessment of bound CMCs.
• the functional surface solves the problem of requiring antibodies as binding agents by using small engineered fusion proteins for capturing cells from body fluids which include non-immunoglobulin binding molecules with specificity for markers on these cells, linkers, an attachment site to a solid support, and a protease cleavage site for gentle cell release from the support and which do not comprise an IgG-Fc part prone to undesired cell interactions.
• a detection device can be configured to detect rare cardiovascular cells(heart, kidney or cerebral) in vivo, which may have a detection area coated with fusion proteins for isolating and/or capturing biological receptor molecules.
• the detection area may include areas that include the structure B-L1-PCS-L2-C, C-L2-PCS-L1-B, B-PCS-L1-C, or B-L1-PCS-C and may be coupled to a guide wire, wherein B is a non-IgG-binding molecule that is capable of binding a diagnostically relevant target wherein the binding of the target enables the isolation and or capturing of cells expressing the target on their surface or of the molecule from body fluid; LI is a first peptide linker for enabling access of the protease to the protease cleavage site; PCS is a protease cleavage site wherein the specific cleavage of the PCS eliminates the covalent bond between the coupling moiety C and the specific binding protein B and releases the captured cells or soluble molecules from the solid support; L2 is a second peptide linker for enabling access of the protease to the protease cleavage
• the guidewire may include a metal, or a polymer.
• the overall length of the guide wire and the functionalized structure is between about 100mm to about 300 mm.
• the diameter of the functionalized structure is between about 0.3mm to about 3 mm.
• the functional area of the probe/guidewire after the collection process can be split (e.g., cut) into a plurality of segments such as 2, 3, 4, or more segments such that the pieces can be subject to different analyses.
• one piece can be utilized for genomic analysis with another piece can be utilized for immunostaining.
• the functional area can include features to facilitate subdivision/splitting/detachment, such as a cut-away, tear-away, perforation line, or other type of mechanical or other detachment (e.g., electrolytic detachment).
• indicia of a desired geometry can be printed onto the functional (e.g., flat) surface(s) of the probe to allow for expedited automatized image-based or other analyses, e.g., of cells or other material.
• a fluid e.g., urine
• a material of interest e.g., cfNA
• One non-limiting example setup is designed for 7 probes with 18 mL or more of urine. It is possible to reduce or to expand the flow system depending on the desired clinical result.
• Set up of an example Flow System for probes can include any number of the following:
• silicone tubes - following lengths can be used as non-limiting examples: lx 25 cm; lx 15 cm; 6x 6 cm; lx 20 cm;
• the long end can be used to aspirate cell suspension from 50 mL test tube, such as, e.g., a FALCON Conical Centrifuge Tube (Thermo Fisher Scientific, Waltham, MA) - put this end in the 50 mL FALCON;
• test tube such as, e.g., a FALCON Conical Centrifuge Tube (Thermo Fisher Scientific, Waltham, MA) - put this end in the 50 mL FALCON;
• the short silicone tube can be used in connection with a 3-way-valve, as illustrated in Figure 9C having 3 positions; a first Position 1; a second Position 2 at a right angle to Position 1; and a third Position 3 at a right angle to Position 2 and spaced about 180 degrees apart from Position 1.
• Position 1 can be used on the 3-way valve to fix the silicon tube, as shown in Figure 9D. Additional 3-way valves can then be prepared.
• Each 6cm silicone tube can be used and connected to 3-way valves at Position 1, as shown in Figure 9E.
• An assembly can be taken and 3-way valve(s) can be plugged in at Position 2, as shown in Figure 9F. This can be repeated for the other assemblies, as shown in Figure 9G.
• a silicone tube (e.g., about 20cm in length) can be used to connected to the 50mL FALCON tube, as shown in Figure 9H. All 3-way valves can then be closed with injection stoppers, as shown in Figure 91, to form a closed loop.
• the system can then be blocked to avoid non-specific binding interactions, such as for Western Blot, ELISA, IHC, and/or nucleic acid detection methods.
• a blocking agent can saturate excess protein-binding sites on membranes and microplates in immunoassays to reduce background interference. For example, 20ml of 3% BSA/PBS (phosphate-buffered saline) can be placed in a 50mL tube.
• the pump can be activated with the appropriate velocity. Once the whole system is filled with the blocking agent, the pump can be stopped and incubation can occur at room temperature for an appropriate period of time, such as about 30 minutes in some cases. The system can be checked for the absence of bubbles. Bubbles present can be manually flicked on the tube to move the bubble to the end of the tube. After blocking, the flow system can be emptied. The pump can be activated, but remove aspirate silicone tube from the 50mL test tube so no further BSA will be aspirated, just air so the system will be soon emptied.
• Figure 9 J illustrates an embodiment that includes a needle/cannula, stopper including a septum, and probe.
• the probes preferably include the stopper (e.g., yellow stopper) in order to close the flow system.
• the needle can then be pushed through the injection stopper in an appropriate direction indicated by the arrow, such as from the top to the bottom, as illustrated in Figure 9K.
• the probe can be gently slid through the cannula in an opposite direction (e.g., bottom to top) as indicated by the arrows, until an appropriate distance is reached, e.g., about 2cm in some cases, before an end of the functional area of the probe, as indicated in Figure 9M. Care is preferably taken to avoid touching or scratching the functional area of the probe with the cannula.
• the cannula is gently removed in the appropriate direction (e.g., bottom to top) through the septum of the injection stopper.
• the first 3-way valve can then be opened by removing the injection stopper, as shown in Figure 90.
• the probe can then be carefully inserted without touching the indwelling surface/inside diameter of the 3-way valve or silicon tube, as shown in Figure 9P. This can be repeated for each of the remaining probes, as shown in Figures 9R-9S.
• the functional part of the probe can be in some cases positioned in the middle of the silicone tube (e.g., 6cm silicone tube).
• the application time can start when all of the probes are inserted in the system, The system can then be incubated for an appropriate period of time, such as about or at least about 30, 45, 60, 75, 90, 120, or more minutes.
• the probes can be removed in the same direction as the insertion direction, taking care to avoid contact with the inside diameter/wall of the 3-way valve or silicone tubing to avoid scratching.
• the probe can then be placed in an appropriate container such as a wash glass, and the 3-way valve closed with its original lid. This process can be repeated for each probe.
• Each probe can be placed in its own wash glass.
• Each probe can then be washed an appropriate number of time, such as twice in some cases, in a solution, such as gently dipping the probe in lx PBS in some embodiments.
• the fusion proteins may include one, two, or more specific IgG or non-IgG binding molecule with specific binding affinity to a target molecule of interest; and/or binding to a diagnostically and/or therapeutically relevant target that may include a tumor cell surface target or soluble molecule such as, for example, EGFR, EpCam, Her2, MUC1, CD146, CD133, CD31, CD34, CD105, B7H1/2/H3/H4, gangliosides, HMW- MAA, PDL-1, PDGFR, IGFR, TGFR, MET, HER2/3, interleukin receptors, adhesion molecules, Ig variable chains, TCR or VEGFR1/VEGFR2; and/or binding affinity to non IgG binding proteins such as ubiquitin, mutein (Affilin), scFv, Darpin, Anticalin, or Fynomer.
• a tumor cell surface target or soluble molecule such as, for example, EGFR, EpCam, Her2, MUC
• the fusion proteins may include a first peptide linker that is not cleavable by proteases present in body fluids, is non-immunogenic, and is, for example, 5-50 amino acids (e.g., 10-30 amino acids) that may be selected from, for example, G, S, A, and/or P.
• a first peptide linker that is not cleavable by proteases present in body fluids, is non-immunogenic, and is, for example, 5-50 amino acids (e.g., 10-30 amino acids) that may be selected from, for example, G, S, A, and/or P.
• the fusion proteins may include a protease cleavage site for a protease which is not present or not effective on the described construct of this invention in the body fluid from which the cells are captured, which may include blood, urine, saliva, and/or cerebral spinal fluid.
• the fusion proteins may include a viral protease cleavage site such as TEV protease cleavage site.
• the fusion proteins may include a second peptide linker that may be identical or different from peptide linker 1, is not cleavable by proteases present in the body fluid, is non-immunogenic, and has 5-50 amino acids (e.g., 10-30 amino acids) that may be selected from G, S, A, and P.
• the fusion proteins may include a coupling moiety, which may have a reactive chemical group that forms covalent bonds with chemical groups of the solid support such as an electrophilic group, a nucleophile group, a redox-active group, a group enabling addition reaction or cyclic addition reaction, Cysteine, NHS, Azide, or Maleimide.
• a coupling moiety which may have a reactive chemical group that forms covalent bonds with chemical groups of the solid support such as an electrophilic group, a nucleophile group, a redox-active group, a group enabling addition reaction or cyclic addition reaction, Cysteine, NHS, Azide, or Maleimide.
• the guide element may be at least partially designed as a wire, may be at least partially resilient, and may be at least partially designed as a flexible medical guide wire.
• the guide element may be at least partially designed as a thread and may be at least partially a flexible plastic thread, or a catheter.
• the guide element may have a receiving portion for receiving at least one functional element.
• the guide element may have a distal end and a proximal end, and in between the distal and proximal ends, the guide element may have a receiving portion adapted to receive at least one functional element.
• the probe can include a body having a length dependent upon the desired access site and the desired placement site for the distal end.
• lengths in the area of from about 1 cm to about 30cm, between about 1cm to about 20cm, between 2cm and about 20cm, between 2cm and about 10cm, or between 5cm and about 20cm can be useful in applications that require the catheter to be advanced down a relatively short tubular access sheath.
• Longer lengths may be used as desired, such as on the order of from about or at least about 120 cm to about 140 cm for use in percutaneous access at the femoral artery for placement of the distal end in the vicinity of the coronary artery.
• Intracranial applications may call for a different catheter shaft length depending upon the vascular access site, as will be apparent to those of skill in the art.
• the guide element is formed at least partially helical.
• the guide element has at its outer periphery at least in part an external thread. [0081] In some embodiments, the guide element has a distal end and a proximal end, said distal end being insertable into a blood vessel or body cavity.
• the guide element has a distal end and a proximal end, wherein the distal end is thickened.
• the guide element has a distal end and a proximal end, wherein the proximal end is connected to a stabilizing element.
• the guide element is screwed into an internal thread of the stabilizing element.
• the guide element is manufactured from a metallic and/or non-metallic material.
• the guide element has at its distal portion a functional detection area equipped with receptors.
• the guide element is connected with a stabilizing element that meets at least one of the following requirements: the stabilizing element is constructed in such a way that it stabilizes at least portions of the guide element; the stabilizing element is made of plastic or metal; the stabilizing element is connected to the proximal end or a proximal end portion of the guide element; the stabilizing element is detachably connected to the guide element; the stabilizing element is uniformly connected with the guide element; the stabilizing element is glued or welded to the guide element; the stabilizing element is at least partially cylindrical; the stabilizing element is at least partially designed as a sleeve; the stabilizing element has at least in part an internal thread; the stabilizing element is at least partially pushed, plugged or screwed onto a proximal portion of the guide element.
• a variety of cell types, molecules, and tumor and biomarkers are present in body fluids. However, it is often not possible to obtain them in sufficient quantity for analysis because they are present in very low concentrations. For diagnostic, prognostic, and scientific research purposes, these rare cells and other biomolecules are of high interest because they can serve as biomarkers of disease progression and diagnosis. For example, one of the leading causes of death worldwide is cancer. Breast, colon, prostate, gastric, hepatic, melanoma and lung tumors are the most common forms of cancer worldwide and in the United States. Having the ability to detect the development of cancer early in the disease process would have a significant impact on the health of the population.
• cancer cells e.g., circulating tumor cells (CTCs)
• CTCs circulating tumor cells
• Biomarkers in body fluids can also be measured periodically to monitor disease progression.
• tumor and other disease biomarkers are often present in low concentrations, they cannot be efficiently recovered by conventional methods of enrichment for analysis by established diagnostic methods of clinical chemistry, pathology, or cytology, as well with imaging technology the tumor has to have a sufficient size to be detected As a result, a patient's disease may remain at a subclinical level for years before it is detected. New methods are needed to achieve early detection of occult cancer cells, which can result in early diagnosis, more aggressive treatment, and improved clinical outcomes.
• Other forms of blood biomarkers are circulating cancer cell free nucleic acids (e.g., DNA, RNA, microRNA).
• Exosomes released from tumor cells and normal cells also detected in circulating form in body fluids. Exosomes are 30 to 200 nm, membrane-bound vesicles that are released by most types of cells, including tumor cells. Exosomes contain a great variety of bioactive molecules, including tumor marker peptides, microRNA, cell surface tumor antigens, mRNA, and DNA. In cancer, tumor cells aberrantly secrete large quantities of exosomes to transport paracrine signals or to contribute to tumor-environment interaction at a distant site. Detection and isolation can be problematic whereby using an in vivo catching device can capture and allow more exosome than traditional blood tube procurement and centrifugation separation techniques which limit type of exosomes isolated.
• Other applications of some embodiments of the invention include collection of infection disease pathogens (virus, fungi, bacteria, parasites, and the like).
• infection disease pathogens virus, fungi, bacteria, parasites, and the like.
• diagnosis Other applications include monitoring patients during therapy, or relapse after being clinically cured. Diagnosis can be important for individuals in some cases who are in contact with patients who have pathogenic infectious disease or exposed in the environment with pathogens present.
• the approach of assessing infectious disease pathogens can be applied to humans and animals. The latter can be quite important in large animal (4 legs) livestock used in the human consumption food chain. Identification of pathogen virus infection at early stages could be a very cost effective and treatment strategy. Early detection of low levels of pathogen in body fluids is limited by current conventional blood tube ⁇ 10ml assessment. The identification of a few infected animals at an early stage can prevent a "herd effect".
• Examples of diagnostic approaches for identifying sepsis patients are generally based on either pathogen detection or evaluation of host response using biomarkers.
• the mainstay and de facto "gold standard" for diagnosis of most bacterial infections, including sepsis, is microbial growth of a causative pathogen followed by taxonomic identification.
• culture -based methods suffer from multiple limitations: (1) positive results usually take >24 h; (2) in clinically confirmed sepsis cases, positive cultures are produced in only -1/3 of blood cultures and -2/3 of all cultures from any site including blood, and, consequently, negative culture results cannot be interpreted definitively; (3) there is a reduced chance of positive culture if the patient is already on antibiotics; (4) interpretation is confounded by false positives produced by contaminants; and (5) positive blood cultures can result from transient bacteremia in the absence of a severe inflammatory response; (6) assessment of rare pathogens circulating at early stages to obtain sufficient amount for downstream assay analysis; (7) obtaining sufficient amount of pathogens to obtain enough sample of pathogen for multiple testing for identification.
• approaches by themselves have inadequate sensitivity, specificity, and predictive value for diagnosing sepsis.
• Systemic inflammation is a whole body reaction having an infection- positive (e.g.,, sepsis) or infection-negative origin. It can be important to distinguish between these two etiologies early and accurately because this can have significant therapeutic implications for critically ill patients. Rapid diagnosis at the earliest stage can be effectively treatable thus some embodiments of the invention can identify at the earliest potential stage of pathogen infection without drawing any significant amount of blood. If bacterial DNA can be detected early in the disease process that can (1) determine which patients with systemic inflammation had sepsis, (2) be robust across independent patient cohorts, (3) be insensitive to disease severity, and (4) provide diagnostic utility.
• Similar approaches to viral diseases can be highly advantageous if one can catch at very early stages in blood; thus more effective in treatment. Examples include rare HIV, Hepatitis virus, dengue virus, influenza virus, rotavirus, Lhassa, hantavirus, EBOLA virus, and other dangerous viruses. Early detection of rare presence of a virus would be very important in diagnosis and activation of immediate treatment. This would save morbidity and health care cost for assessing high risk patients. Also advantageous in some embodiments is diagnosis of a viral infection with sufficient virus pathogen to assess the infection. Identification and collection of patients with pulmonary pneumonia symptoms that need to be determined if bacterial or virus infection. Often problem is enough sample of blood for performing downstream identification assays rapidly before full blown infection occurs. Rapid decision for immediate therapeutic albeit antibiotic or viral targeted can be valuable.
• Endothelial progenitor cells are a group of heterogeneous cell population capable of differentiating into the endothelial lineage.
• cardiovascular diseases such as hypertension, hyperlipidemia, coronary heart disease and stroke.
• vascular endothelial dysfunction is closely correlated with the development of hypertension.
• the factors accounting for endothelial dysfunction in hypertension are very complicated, but reduction in EPCs numbers and function is believed to play a key role in this regard.
• SHR spontaneously hypertensive rats
• CMOS myocardial cell necrosis
• biomarkers include creatine phosphokinase of muscle band (CPK-MB) and troponins for myocardial necrosis, brain natriuretic peptide for left ventricular overload and C-reactive protein (CRP) for inflammation; however, these markers have several shortcomings.
• the diagnostic specificity of brain natriuretic peptide and CRP is low.
• Troponin levels remain low in many cases of non-ST-elevation ACS, and initial findings may be negative in some high-risk patients depending on the time of sampling, assay sensitivity, marker release, and clearance kinetics. These problems can delay proper diagnosis and care.
• ACS non-ST-elevation ACS
• CECs circulating endothelial cells
• CEC counts are very low in normal individuals, elevated counts have been documented in a variety of vascular disorders.
• An increased CEC level can be detected in patients with ACS and low numbers in subjects with effort angina or noncoronary chest pain.
• An elevation of CECs may identify a subgroup of ACS patients with an initially normal troponin level.
• the isolation of CECs from the peripheral blood thus can be an early, specific, independent diagnostic marker for non- ST-elevation ACS.
• CEC also assessed in neurostroke and kidney disease damage assessment.
• cfNA circulating free nucleic acids
• Other applications include the detection of circulating free nucleic acids (cfNA) in the form of DNA, mRNA, histone bound DNA, and microRNA. Detection of these cancer specific or infectious disease related cfNA would allow early detection, monitoring patients being treated or non treated, identification of genotype changes in cancer or pathogen. Detection of cfNA can be by probe techniques such as peptide nucleic acid (PNA), BNA, LNA, XNA are for DNA and RNA hybridization, or related type DNA or peptide analogue probes or antibodies.
• PNA peptide nucleic acid
• BNA peptide nucleic acid
• LNA LNA
• XNA XNA
• PNA or related synthetic(LNA,BNA, XNA, aptamers) probes is flexible and the incorporation of chiral units along the carbon chains of the molecule backbone provide unique molecular configurations for the functional group and solid surface attachment.
• PNA probes which are bound to the collection device from PNA- DNA complementary duplexes according to Watson-Crick base pairing rules have higher affinity and sequence selectivity compared to conventional DNA-DNA duplex hybridization.
• nucleosomes can also be detected using systems and methods as disclosed herein.
• the nucleosome is the basic unit of chromatin structure and consists of a protein complex of eight highly conserved core histones (comprising a pair of each of the histones H2A, H2B, H3, and H4). Around this complex is wrapped approximately 146 base pairs of DNA.
• Another histone, HI or H5 acts as a linker and is involved in chromatin compaction. Status of histones methylation or acetylation can be assessed on isolation to determine disease related changes compared to normal.
• the DNA is wound around consecutive nucleosomes in a structure often said to resemble "beads on a string" and this forms the basic structure of open or euchromatin. In compacted or heterochromatin this string is coiled and super coiled into a closed and complex structure.
• CTC metastatic cells
• other biomarkers from body fluids.
• CTC metastatic cells
• the enrichment of specific cells, especially CTC is possible from a blood sample of a patient using commercially available paramagnetic nanoparticles and/or density gradient centrifugation.
• One of these commercial methods is a test in which cells such as CTCs can be enriched from 7.5 ml of blood by paramagnetic nanoparticles, which enables observations about the disease process.
• the cells can only be collected in very limited quantities, which may be insufficient for analysis.
• the nanoparticles can irreversibly penetrate or bind to the cells, thereby contaminating the sample and affecting the diagnostic steps that follow the collection.
• antibodies directed against a specific cell-surface marker can be covalently or otherwise coupled to a solid support which serves as a capturing device.
• Antibodies are large complex molecules that can be covalently attached to a binding surface such as beads by different types of chemistries. Most often lysine-based coupling is performed leading to unspecified and multiple attachment sites. Cleavage of the antibody by unspecified proteases is not possible since this would harm the cells of interest that are to be captured. Additionally, cells captured via such approaches bind tightly to the solid support of the capturing device, e.g. (magnetic) beads, foams, wire, polymers, etc. The gentle release of cells for further analysis (e.g.
• the constant part of antibodies can engage in cell contacts independent of the specificity of the variable domain directed against the specific cell surface marker and can lead to capturing of undesired cells, thus reducing the specificity of the cell capturing.
• the engineering and expression of antibodies can also be cumbersome and difficult.
• detection and/or collection systems as disclosed herein can include any number of the following features:
• a wire comprising a functional member comprising a proximal end, a distal end, a first flat surface and a second flat surface opposing the first surface, the functional member configured to fit within a body lumen, wherein the functional member comprises binding elements configured to bind circulating biomaterials of interest, wherein the functional member comprises curved portions that form revolutions around the longitudinal axis of the device;
• the wire comprises from about 3 revolutions to about 5 revolutions per 1 cm of length of the wire;
• the wire comprises about 4 revolutions per 1 cm of length of the wire
• the wire comprises a metal
• the metal comprises stainless steel
• the metal comprises Nitinol
• a proximal handle that does not comprise binding elements
• the functional member comprises a third surface and a fourth surface, the third surface and the fourth surface each adjacent the first surface and the second surface;
• third surface and the fourth surfaces are flat surfaces, or not flat surfaces
• third surface and the fourth surfaces do not comprise binding elements
• a collar operably connected to the proximal end of the functional member, the collar configured to stably position the device within a body lumen;
• the functional member has a non-circular, square, and/or rectangular cross-section
• a filter operably connected to the collar to isolate cells according to their size it also can change the blood flow;
• binding elements comprise fusion proteins also biological probes or synthetic material probes;
• functional member is transformable from a first curved configuration to a second configuration more linear than the first configuration
• second configuration has a greater axial length than the first configuration
• At least part of the device is transformable from the second configuration to the first configuration via exposure to body temperature
• flaps comprise apertures configured to filter blood
• flaps are movable between a first radially compressed configuration to a second radially expanded configuration
• functional member comprises a bifunctionally charged carrier
• control line runs at least partially through one or more eyelets on the functional member
• control line runs at least partially through one or more apertures on the functional member
• functional surface/binding surface does not include an increased surface area (e.g., lacks pores and/or a micro structure);
• functional surface/binding surface includes a smooth, uninterrupted, and/or continuous surface
• probe and/or wire segment includes, or does not include any of the following structures: a spiral, screw-shaped, worm-shaped, undulated, helical, filamentous, brush-like, comb-like, net-like, porous, spongy or similar structures.
• actions such as “detecting and/or reversibly capturing cells, molecules, and other biomaterials from body fluids in vivo over time” includes “instructing the detecting and/or reversibly capturing cells, molecules, and other biomaterials from body fluids in vivo over time.”
• the ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof.
• Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited.
• the terms “approximately”, “about”, and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount.

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